Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.
Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.
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DOI：
10.1083/jcb.201008167
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发表时间：
2011-02-21
期刊：
影响因子：
--
通讯作者：
Kroemer G
中科院分区：
文献类型：
--
作者：
Morselli E;Mariño G;Bennetzen MV;Eisenberg T;Megalou E;Schroeder S;Cabrera S;Bénit P;Rustin P;Criollo A;Kepp O;Galluzzi L;Shen S;Malik SA;Maiuri MC;Horio Y;López-Otín C;Andersen JS;Tavernarakis N;Madeo F;Kroemer G
乙酰化酶抑制剂亚精胺和 Sirtuin-1 激活剂白藜芦醇会破坏调节自噬的乙酰化酶和脱乙酰化酶的拮抗网络。自噬可以保护细胞器、细胞和生物体免受多种应激条件的影响。白藜芦醇诱导自噬需要烟酰胺腺嘌呤二核苷酸依赖性脱乙酰酶 Sirtuin 1 (SIRT1)。在本文中，我们证明乙酰化酶抑制剂亚精胺可以独立于人类和酵母细胞以及线虫中的 SIRT1 刺激自噬。尽管白藜芦醇和亚精胺通过不同的机制引发自噬，但这些化合物刺激收敛途径，最终导致乙酰蛋白质组的一致修饰。两种试剂分别有利于细胞质和细胞核中的趋同脱乙酰化和乙酰化反应。白藜芦醇和亚精胺都能够诱导细胞质（去核细胞）中的自噬。此外，SIRT1 的细胞质限制突变体可以刺激自噬，表明细胞质脱乙酰化反应决定自噬级联反应。在白藜芦醇和亚精胺均不能单独刺激自噬的剂量下，这些药物协同诱导自噬。总而言之，这些数据强调了可以药理学操作的拮抗性脱乙酰酶和乙酰酶的自噬调节网络的重要性。
The acetylase inhibitor spermidine and the sirtuin-1 activator resveratrol disrupt the antagonistic network of acetylases and deacetylases that regulate autophagy. Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide–dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.
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